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. 2018 Nov 2;1(7):e184169.
doi: 10.1001/jamanetworkopen.2018.4169.

Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia

Sara Barmettler  1 , Mei-Sing Ong  2 , Jocelyn R Farmer  1 , Hyon Choi  3 , Jolan Walter  4   5
Affiliations

Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia

Sara Barmettler et al. JAMA Netw Open. .

Abstract

Importance: Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality.

Objective: To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality.

Design, setting, and participants: A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System).

Exposures: Rituximab administration.

Main outcomes and measures: The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use.

Results: Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P < .001). In the survival analysis, increased mortality was associated with increasing age (hazard ratio [HR], 1.02; 95% CI, 1.01-1.02; P < .001), male sex (HR, 1.14; 95% CI, 1.02-1.28; P = .02), and severe infectious complications in the 6 months before (HR, 3.14; 95% CI, 2.77-3.55; P < .001) and after (HR, 4.97; 95% CI, 4.41-5.60; P < .001) the first rituximab infusion. A total of 201 patients (4.5%) received immunoglobulin replacement following rituximab, and among these patients, higher cumulative immunoglobulin replacement dose was associated with a reduced risk of serious infectious complications (HR, 0.98; 95% CI, 0.96-0.99; P = .002).

Conclusions and relevance: Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barmettler reported receiving an investigator-initiated publication and research grant from CSL Behring during the conduct of the study; grants from Immune Deficiency Foundation Research Grant, grants from Shire Research Grant, and grants from Biocryst Research Grant outside the submitted work. Dr Walter reported receiving an investigator-initiated publication and research grant from CSL Behring, personal fees from CSL Behring, and personal fees from Shire outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Immunoglobulin G (IgG) Levels 18 Months After Initiation of Rituximab Therapy
Levels of IgG after initiation of rituximab therapy in patients with pretherapy status of normogammaglobulinemia (n = 342) (A), mild hypogammaglobulinemia (n = 91) (B), moderate hypogammaglobulinemia (n = 65) (C), and severe hypogammaglobulinemia (n = 157) (D). Error bars indicate 95% CI.
Figure 2.
Figure 2.. Severe Infection Rates Following Initiation of Rituximab Therapy
Infection rates in patients during treatment of cancer (n = 3478) (A), rheumatologic disease (n = 1241) (B), common variable immunodeficiency (CVID) (n = 57), and hematologic disease (n = 340) (D); pretreatment immunoglobulin G (IgG) levels within the reference range (n = 342) (E), showing hypogammaglobulinemia (F), or that were not determined (n = 3824) (G); and comparison of severe infection rates among patients who received immunoglobulin (IgR) replacement therapy (n = 201) and those who did not (n = 4278) in the 6 months following rituximab use (H). Error bars indicate 95% CI.
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